EP1032379B1 - Composition with azelaic acid - Google Patents
Composition with azelaic acid Download PDFInfo
- Publication number
- EP1032379B1 EP1032379B1 EP98962351A EP98962351A EP1032379B1 EP 1032379 B1 EP1032379 B1 EP 1032379B1 EP 98962351 A EP98962351 A EP 98962351A EP 98962351 A EP98962351 A EP 98962351A EP 1032379 B1 EP1032379 B1 EP 1032379B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- concentration
- weight
- composition according
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Definitions
- the invention relates to a composition with azelaic acid in one Hydrogel the Can be used as medicines.
- This registration takes German priorities DE 197 53 044 with the filing date of November 19, 1997 and DE 198 08 086 with the filing date of February 20, 1998.
- US-SN 60 / 074.850 with the filing date of 12 February 1998 claimed as an additional priority.
- EP 0 336 880 A2. which was registered on March 29, 1998 becomes a Pharmaceutical composition described, which consists of (i) azelaic acid in a concentration of 20 percent by weight, from (iii) triacylglycerides and diacylglycerides, from (iv) propylene glycol. from (v) polysorbate, for Example polyethylene (20) sorbitan monooleate, and from (vii) water and salts,
- This topically administered composition is used to treat various age-related changes in the facial skin.
- the composition is in the form of a cream.
- Azelaic acid is also known also against inflammatory and infectious dermatoses, such as acne and rosacea. to use.
- composition describes a pharmaceutical composition.
- the as an adjuvant is used for a vaccine.
- This composition is said to Replace Freund's adjuvant. It is injected.
- pharmaceutical The active ingredient is, for example, hepatitis B surface proteins.
- polyacrylic acid (iii) triacylglycerides and / or diacylglycerides, such as MIGLYOL, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN. EMULROR and SIMULSOL M-53 used.
- soy lecithin added is a (vii) aqueous phase with Salt.
- the composition is not administered topically.
- the emulsion has particles in the size of 0.03 to 0.5 ⁇ m, preferably 0.05 to 0.2 ⁇ m.
- Emulsion for the administration of biologically active substances on the surface of the skin is present.
- This composition contains particles of one size from 30 to 500 nm. Preferably 70 to 200 nm.
- active pharmaceutical ingredients anti-inflammatory drugs are used, for example.
- Farther ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides.
- the composition is a (vii) aqueous phase with salts.
- the Composition is administered topically.
- the composition according to the invention has the advantage that it is a higher amount of active pharmaceutical ingredient in living skin layers and / or skin appendages.
- the availability of the Azelaic acid in the composition according to the invention by the factors three to five higher than the azelaic acid cream according to the state of the art Technology. This availability was determined in a FRANZ flow diffusion cell - Test demonstrated, which is shown in detail in the examples becomes.
- Especially the living skin layers and / or skin appendages are the desired destinations for azelaic acid. It is particularly good Use composition with azelaic acid in high concentrations.
- composition which can be administered topically is advantageous.
- the presence of polyacrylic acid is essential. It is for the emergence of the Hydrogel crucial.
- Soy lecithin is preferred as lecithin in the gel.
- the lecithin or soy lecithin is at a maximum concentration of 3 Weight percent advantageous. More preferably a concentration of at most 1.5 percent by weight and most preferably one Concentration of at most 1 percent by weight. The last concentration causes the hydrogel to no longer exist as a nanoemulsion.
- composition according to the invention at lecithin concentrations of one percent by weight and less forms no classic nanoemulsion according to the prior art. Rather, there is a gel that has a homogeneous mass with practically none Vesicles, but includes membrane fragments. That azelaic acid and the rest the composition did not form a nanoemulsion could not be foreseen. Clarity was only possible with the help of scanning electron microscope images be created. It turned out that no nanoemulsion at microscopic Consideration is to be identified.
- the composition according to the invention a high penetration into living Layers of skin and / or skin appendages, which do not apply to creams watch is
- Polyacrylic acid is an anionic polymer made from acrylic acid that is only partially soluble in water.
- the one percent aqueous suspension has a pH of 3 and almost the same viscosity as water. Gel formation and the formation of highly viscous products only occur when neutralized with inorganic or organic bases.
- Rudolf VOIGT and Manfred BORNSCHEIN 1979, textbook on pharmaceutical technology, page 314.
- VEB Verlag Volk und Pass Berlin. Compare also Rompp. Chemistry lexicon. Edited Jürgen FALBE and Manfred REGNITZ. 1992, 9th edition. Page 3508. Thieme Verlag Stuttgart, ISBN 3-13-735009-3.
- Triglyceride is a term for esters of glycerol, the three hydroxyl groups of which are esterified by carboxylic acids.
- the naturally occurring fats and fatty oils are triglycerides ("neutral fats"), which usually contain different fatty acids in the same glycerol molecule. J. Am.- Oil. Chem Soc. Vol 62, page 730, (1985); and perfume. Cosmetics Vol 58, page 353, (1977); and Römpp, Chemie Lexikon, Ed. Jürgen FALBE and Manfred REGNITZ. 1990. 9th edition. Pages 1339 - 1342. Thieme Verlag Stuttgart, ISBN 3-13-734709-2.
- Propylene glycol is in HP FIEDLER: Lexicon of auxiliaries. 4th edition. 1996, ISBN 3-87193-173 on pages 1278 to 1282.
- Lecithins are extracted from biological material.
- a lecithin fraction from soybeans (the most common raw material) comprises, for example, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid and the like. Linolenic acid. Normally the saturated fatty acid is esterified with the primary, the unsaturated with the secondary hydroxy group of the glycerol.
- Lecithins are components of the cell membranes of all living things. Lecithins initially swell in water like lyophilic colloids. Later, they represent transparent, colloidal solutions. Depending on the water content, they form different textures, whereby the lamellae are formed from lipid double layers. With higher water content, liposomes are formed.
- a gel is characterized by the following properties: It is a dimensionally stable, easily deformable, liquid and possibly gas-rich, disperse system consisting of at least two components. Rompp. Chemistry Lexicon, Ed. Jürgen FALBE and Manfred REGNITZ, 1990, 9th edition, page 1511, Thieme Verlag Stuttgart, ISBN 3-13-734709-2; and Pharm. Republicer Zeit Vol. 8, pages 179 to 188. (1979): and perfume. Kosmet .. Vol. 58, pages 251 to 253 (1977)
- Preservatives can be contained in the aqueous phase.
- Preservatives include, for example, benzoic acid. Because of its antimicrobial properties, benzoic acid is particularly suitable as a preservative.
- composition of the invention shows and is pharmacological can be used as a therapeutic agent or as a medication.
- composition according to the invention is preferred together with at least one physiologically compatible, pharmacological auxiliary or carrier.
- Pharmacological adjuvants and vehicles are described in Remington's Pharmaceutical Science, 15 th ed. Mack Publishing Company, Easton Pennsylvania (1980).
- the appropriate dose for these therapeutic effects is different and depends, for example, on the concentration of the individual elements in the pharmaceutical Composition, the host, the mode of administration and the Type and severity of the conditions to be treated
- composition of the invention can be compared with those in the galenic pharmacy usual additives and / or carriers according to known methods processed to the usual topical forms of application become.
- a pharmaceutical composition containing azelaic acid has the following recipe and the following process steps:
- Benzoic acid and EDTA are in common concentrations in 60 to 70 parts Water dissolved. Then a mixture of 1 part medium chain Triglycerides and 1.5 parts of polysorbate 80 are added with stirring and homogenized (pre-emulsion). 1 part of lecithin is in 12 parts of propylene glycol brought in. The resulting solution is stirred into the pre-emulsion and homogenized. After adding 1 part of polyacrylic acid, 15 parts Azelaic acid introduced into the resulting pharmaceutical composition. Then the gel former is aligned with the necessary one Amount of sodium hydroxide solution. The resulting gel has an approximately 4 times higher availability of azelaic acid in living skin layers and / or skin appendages.
- the time course of the 14 C-azelaic acid was measured in the acceptor medium (Hepes Hanks Balanced Salt Solution: HHBSS), which flows under the skin, at two-hour intervals over a period of 24 hours. Furthermore, at the end of each experiment the radioactivity on the skin surface, in the stratum corneum and in the rest of the skin was determined. In order to investigate the metabolism of azelaic acid in the skin, skin extracts and selected fractions of acceptor medium were examined by means of radiochromatography (HPLC and radiometric detection).
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
Die Erfindung, betrifft eine Zusammensetzung mit Azelainsäure in einem Hydrogel die als Arzneimitte verwendet werden Kann. Diese Anmeldung nimmt die deutschen Prioritäten DE 197 53 044 mit dem Anmeldetag vom 19. November 1997 und DE 198 08 086 mit dem Anmeldetag vom 20. Februar 1998 in Anspruch. Für die USA wird die US - Hinterlegung US-SN: 60/074.850 mit dem Einreichungsdatum vom 12 Februar 1998 ais zusätzliche Priorität beansprucht.The invention relates to a composition with azelaic acid in one Hydrogel the Can be used as medicines. This registration takes German priorities DE 197 53 044 with the filing date of November 19, 1997 and DE 198 08 086 with the filing date of February 20, 1998. For the USA the US deposit US-SN: 60 / 074.850 with the filing date of 12 February 1998 claimed as an additional priority.
In der EP 0 336 880 A2. die am 29.3.1998 angemeldet worden ist, wird eine pharmazeutische Zusammensetzung beschrieben, die besteht aus (i) Azelainsäure in einer Konzentration von 20 Gewichtsprozenten, aus (iii) Triacylglyceriden und Diacylglyceriden, aus (iv) Propylenglycol. aus (v) Polysorbat, zum Beispiel Polyethylen(20)sorbitanmonooleat, und aus (vii) Wasser und Salzen, Diese topisch zu verabreichende Zusammensetzung wird zur Behandlung von verschiedenen altersbedingten Veränderungen der Gesichtshaut eingesetzt. Die Zusammensetzung liegt als Creme vor. Bekannt ist weiterhin, die Azelainsäure auch gegen entzündliche und infektiöse Dermatosen, wie zum Beispiel Akne und Rosazea. einzusetzen.In EP 0 336 880 A2. which was registered on March 29, 1998 becomes a Pharmaceutical composition described, which consists of (i) azelaic acid in a concentration of 20 percent by weight, from (iii) triacylglycerides and diacylglycerides, from (iv) propylene glycol. from (v) polysorbate, for Example polyethylene (20) sorbitan monooleate, and from (vii) water and salts, This topically administered composition is used to treat various age-related changes in the facial skin. The The composition is in the form of a cream. Azelaic acid is also known also against inflammatory and infectious dermatoses, such as acne and rosacea. to use.
In der Roten Liste von 1996 (ISBN 3 - 87193 - 167 -5) wird unter der Nummer 32 282 eine pharmazeutische Zusammensetzung mit dem Namen Skinoren® beschrieben, die besteht aus (i) Azelainsäure in einer Konzentration von 20 Gewichtsprozenten, aus (iii) Triacylglyceriden und Diacylglyceriden aus (iv) Propylenglycol, aus (v) Polysorbat, zum Beispiel Macrogolstrearat 1000 und aus (vii) Wasser und Salzen. Diese topisch zu verabreichende Zusammensetzung wird zur Behandlung von Akne eingesetzt. Die Zusammensetzung liegt als Creme vor. Dieses Dokument wird als nächster Stand der Technik angesehen.In the 1996 red list (ISBN 3 - 87193 - 167 -5) is under the number 32 282 describes a pharmaceutical composition with the name Skinoren®, which consists of (i) azelaic acid in a concentration of 20 Weight percentages, from (iii) triacylglycerides and diacylglycerides from (iv) Propylene glycol, from (v) polysorbate, for example macrogol strearate 1000 and from (vii) water and salts. This topical composition is used to treat acne. The composition is as Cream before. This document is considered the state of the art.
Die internationale Anmeldung WO 96/11700, die am 29. Oktober 1993 hinterlegt worden ist. beschreibt eine pharmazeutische Zusammensetzung. die als Hilfsstoff für einen lmpfstoff eingesetzt wird. Diese Zusammensetzung soll das Freund'sche Adjuvanz ersetzen. Sie wird injiziert. Als (i) pharmazeutischer Wirkstoff wird zum Beispiel Hepatitis B Oberflächen - Proteine eingesetzt. Weiterhin werden (ii) Polyacrylsäure, (iii) Triacylglyceride und / oder Diacylglyceride, wie MIGLYOL, (iv) Propylenglycol, und (v) Polysorbate in Form von TWEEN. EMULROR und SIMULSOL M-53 verwendet. Ebenfalls wird (vi) Sojalecithin hinzugegeben. Die Zusammensetzung ist eine (vii) wäßrige Phase mit Salzen. Die Zusammensetzung wird nicht topisch verabreicht. Die Emulsion weist Partikel in der Größe von 0,03 bis 0,5 µm auf, bevorzugt 0.05 bis 0,2 µm.International application WO 96/11700 filed on October 29, 1993 has been. describes a pharmaceutical composition. the as an adjuvant is used for a vaccine. This composition is said to Replace Freund's adjuvant. It is injected. As (i) pharmaceutical The active ingredient is, for example, hepatitis B surface proteins. (Ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides, such as MIGLYOL, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN. EMULROR and SIMULSOL M-53 used. Also (vi) soy lecithin added. The composition is a (vii) aqueous phase with Salt. The composition is not administered topically. The emulsion has particles in the size of 0.03 to 0.5 µm, preferably 0.05 to 0.2 µm.
Die internationale Anmeldung WO 95/05163. die am 5. August 1994 hinterlegt worden ist, beschreibt eine pharmazeutische Zusammensetzung, die als Emulsion zur Verabreichung von biologisch aktiven Substanzen auf der Hautoberfläche vorliegt. Diese Zusammensetzung enthält Partikel von einer Größe von 30 bis 500 nm. bevorzugt 70 bis 200 nm. Als (i) pharmazeutische Wirkstoffe werden zum Beispiel anti - inflamatorische Medikamente eingesetzt. Weiterhin werden (ii) Polyacrylsäure, (iii) Triacylglyceride und / oder Diacylgiyceride. (iv) Propylenglycol, und (v) Polysorbate in Form von TWEEN. EMULROR, TRITON X und SIMULSOL M-53 verwendet. Ebenfalls wird (vi) Sojalecithin hinzugegeben. Die Zusammensetzung ist eine (vii) wäßrige Phase mit Salzen. Die Zusammensetzung wird topisch verabreicht.The international application WO 95/05163. which deposited on August 5, 1994 has been described as a pharmaceutical composition Emulsion for the administration of biologically active substances on the surface of the skin is present. This composition contains particles of one size from 30 to 500 nm. Preferably 70 to 200 nm. As (i) active pharmaceutical ingredients anti-inflammatory drugs are used, for example. Farther (ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides. (iv) Propylene glycol, and (v) polysorbates in the form of TWEEN. EMULROR, TRITON X and SIMULSOL M-53 are used. Soy lecithin is also added. The composition is a (vii) aqueous phase with salts. The Composition is administered topically.
Die europäische Patentanmeldung EP 0 696 452, die am 26. Juli 1995 hinterlegt worden ist, beschreibt eine Nanoemulsion, die als Medikament zur Behandlung der Augen eingesetzt wird, wobei die Nanoemulsion als topisch aufzutragende Augentropfen verabreicht wird. Diese Zusammensetzung enthält Partikel von einer mittleren Größe von 520 nm. Als (i) pharmazeutische Wirkstoffe werden zum Beispiel anti - inflamatorische Medikamente eingesetzt. Weiterhin werden (ii) Polyacrylsäure, (iii) Triacylglyceride und / oder Diacylglyceride, (iv) Propylenglycol, und (v) Polysorbate in Form von Polyoxyethylenpolyoxypropylen Copolymere verwendet. Die Zusammensetzung ist eine (vii) wäßrige Phase mit Salzen. Die Zusammensetzung wird topisch verabreicht.European patent application EP 0 696 452, filed on July 26, 1995 has been describing a nanoemulsion used as a medication for treatment of the eyes, the nanoemulsion being applied topically Eye drops is administered. This composition contains particles of an average size of 520 nm. As (i) pharmaceutical active ingredients for example anti-inflammatory drugs. Continue to be (ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides, (iv) Propylene glycol, and (v) polysorbates in the form of polyoxyethylene polyoxypropylene Copolymers used. The composition is a (vii) aqueous phase with salts. The composition is administered topically.
Es stellt sich die Aufgabe, eine pharmazeutische Zusammensetzung mit Azelainsäure als therapeutischen Wirkstoff anzubieten. wobei die Bioverfügbarkeit der Azelainsäure gesteigert sein soll. It has the task of having a pharmaceutical composition Offer azelaic acid as a therapeutic agent. being the bioavailability the azelaic acid is said to be increased.
Bei einer Zusammensetzung gemäß dem Stand der Technik die folgenden
Merkmale umfassend:
daß die Zusammensetzung als weitere Zusätze
that the composition as further additives
Die Zusammensetzung gemäß der Erfindung weist den Vorteil auf, daß sie eine höhere Menge an pharmazeutischern Wirkstoff in lebende Hautschichten und / oder Hautanhangsorganen gelangen läßt. Hierbei liegt die Verfügbarkeit der Azelainsäure bei der erfindungsgemäßen Zusammensetzung um die Faktoren drei bis fünf höher als bei der Azelainsäure - Creme gemäß dem Stand der Technik. Diese Verfügbarkeit wurde in einem FRANZ - Durchfluß-Diffusionszell - Test nachgewiesen, der in den Beispielen ausführlich dargestellt wird. Gerade die lebenden Hautschichten und / oder Hautanhangsorgane sind der gewünschten Zielorte für Azelainsäure. Besonders gut ist die Zusammensetzung bei Azelainsäure in hohen Konzentrationen einzusetzen.The composition according to the invention has the advantage that it is a higher amount of active pharmaceutical ingredient in living skin layers and / or skin appendages. The availability of the Azelaic acid in the composition according to the invention by the factors three to five higher than the azelaic acid cream according to the state of the art Technology. This availability was determined in a FRANZ flow diffusion cell - Test demonstrated, which is shown in detail in the examples becomes. Especially the living skin layers and / or skin appendages are the desired destinations for azelaic acid. It is particularly good Use composition with azelaic acid in high concentrations.
Vorteilhaft ist eine Zusammensetzung, welche topisch verabreichbar ist.A composition which can be administered topically is advantageous.
Bevorzugt ist eine erfindungsgemäße Zusammensetzung, bei der die Azelainsäure in einer Konzentration von 5 bis 20 Gewichtsprozent, mehr bevorzugt in einer Konzentration von 10 bis 18 Gewichtsprozent und am meisten bevorzugt in einer Konzentration von 14 bis 16 Gewichtsprozent vorliegt. A composition according to the invention in which the azelaic acid is preferred in a concentration of 5 to 20 weight percent, more preferably in a concentration of 10 to 18 weight percent and most preferred is present in a concentration of 14 to 16 percent by weight.
Wesentlich ist die Gegenwart von Polyacrylsäure. Sie ist für das Entstehen des Hydrogels entscheidend. In dem Gel ist als Lecithin das Sojalecithin bevorzugt. Das Lecithin oder Sojalecithin ist in einer Konzentration von höchstens 3 Gewichtsprozenten vorteilhaft. Mehr bevorzugt eine Konzentration von höchstens 1,5 Gewichtsprozenten und am meisten bevorzugt eine Konzentration von höchstens 1 Gewichtsprozent. Die letzte Konzentration bewirkt, daß das Hydrogel nicht mehr als Nanoemulsion vorliegt.The presence of polyacrylic acid is essential. It is for the emergence of the Hydrogel crucial. Soy lecithin is preferred as lecithin in the gel. The lecithin or soy lecithin is at a maximum concentration of 3 Weight percent advantageous. More preferably a concentration of at most 1.5 percent by weight and most preferably one Concentration of at most 1 percent by weight. The last concentration causes the hydrogel to no longer exist as a nanoemulsion.
Unerwartet hat sich herausgestellt, daß die erfindungsgemäße Zusammensetzung bei Konzentrationen an Lecithin von einem Gewichtsprozent und weniger keine klassische Nanoemulsion gemäß dem Stand der Technik bildet. Vielmehr liegt ein Gel vor, welches eine homogene Masse mit praktisch keinen Vesikeln, jedoch Membranfragmenten umfaßt. Daß Azelainsäure und der Rest der Zusammensetzung keine Nanoemulsion bilden, war nicht vorauszusehen. Erst mit Hilfe von Raster ― Elektronenmikroskop - Aufnahmen konnte Klarheit geschaffen werden. Es stellte sich heraus, daß keine Nanoemulsion bei mikroskopischer Betrachtung zu identifizieren ist. Vorteilhafter Weise besitzt die erfindungsgemäße Zusammensetzung eine hohe Penetration in lebende Hautschichten und / oder Hautanhangsorganen, die bei Cremen nicht zu beobachten istIt has unexpectedly been found that the composition according to the invention at lecithin concentrations of one percent by weight and less forms no classic nanoemulsion according to the prior art. Rather, there is a gel that has a homogeneous mass with practically none Vesicles, but includes membrane fragments. That azelaic acid and the rest the composition did not form a nanoemulsion could not be foreseen. Clarity was only possible with the help of scanning electron microscope images be created. It turned out that no nanoemulsion at microscopic Consideration is to be identified. Advantageously, the composition according to the invention a high penetration into living Layers of skin and / or skin appendages, which do not apply to creams watch is
Bevorzugt ist eine Zusammensetzung, bei der die einzelnen Parameter unabhängig
voneinander die folgenden Konzentrationen aulweisen können:
Die Bestandteile sind selbstverständlich so aufeinander abzustimmen, daß eine Summe von 100% erzielt wird. The components are of course to be coordinated so that one Sum of 100% is achieved.
Am meisten bevorzugt ist eine Zusammensetzung, bei der die einzelnen Parameter
unabhängig voneinander die folgenden Konzentrationen aufweisen
können:
Die Bestandteile sind selbstverständlich so aufeinander abzustimmen, daß eine Summe von 100% erzielt wird.The components are of course to be coordinated so that one Sum of 100% is achieved.
Azelainsäure und deren Herstellung ist in dem deutschen Patent DE 28 17 133.7 beschrieben. Vergleiche auch Römpp, Chemie Lexikon. Herausgeb. Jürgen FALBE und Manfred REGNITZ. 1989, 9. Auflage. Seite 323. Thieme Verlag Stuttgart, ISBN 3-13-734609-6. Azelaic acid and its preparation is described in German patent DE 28 17 133.7. See also Römpp, Chemie Lexikon. Edited Jürgen FALBE and Manfred REGNITZ. 1989, 9th edition. Page 323. Thieme Verlag Stuttgart, ISBN 3-13-734609-6.
Polyacrylsäure stellt ein anionenaktives Polymerisat aus Akrylsäure dar, das in Wasser nur zum Teil löslich ist. Die einprozentige wäßrige Suspension besitzt einen pH-Wert von 3 und annähernd gleiche Viskosität wie Wasser Erst beim Neutralisieren mit anorganischen oder organischen Basen kommt es zur Gelbildung und zum Entstehen hochviskoser Produkte. Rudolf VOIGT und Manfred BORNSCHEIN, 1979, Lehrbuch der pharmazeutischen Technologie, Seite 314. VEB Verlag Volk und Gesundheit Berlin. Vergleiche auch Römpp. Chemie Lexikon. Herausgeb. Jürgen FALBE und Manfred REGNITZ. 1992, 9. Auflage. Seite 3508. Thieme Verlag Stuttgart, ISBN 3-13-735009-3. Polyacrylic acid is an anionic polymer made from acrylic acid that is only partially soluble in water. The one percent aqueous suspension has a pH of 3 and almost the same viscosity as water. Gel formation and the formation of highly viscous products only occur when neutralized with inorganic or organic bases. Rudolf VOIGT and Manfred BORNSCHEIN, 1979, textbook on pharmaceutical technology, page 314. VEB Verlag Volk und Gesundheit Berlin. Compare also Rompp. Chemistry lexicon. Edited Jürgen FALBE and Manfred REGNITZ. 1992, 9th edition. Page 3508. Thieme Verlag Stuttgart, ISBN 3-13-735009-3.
"Triglycerid" ist eine Bezeichnung für Ester des Glycerins, dessen drei Hydroxy-Gruppen durch Karbonsäuren verestert sind. Die natürlich vorkommenden Fette und fetten Öle sind Triglyceride ("Neutralfette"), die in der Regel verschiedene Fettsäuren im gleichen Glycerin-Molekül enthalten. J. Am.- Oil. Chem Soc. Vol 62, Seite 730, (1985); und Parfüm. Kosmet. Vol 58, Seite 353, (1977); und Römpp, Chemie Lexikon, Herausgeb. Jürgen FALBE und Manfred REGNITZ. 1990. 9. Auflage. Seiten 1339 - 1342. Thieme Verlag Stuttgart, ISBN 3-13-734709-2. "Triglyceride" is a term for esters of glycerol, the three hydroxyl groups of which are esterified by carboxylic acids. The naturally occurring fats and fatty oils are triglycerides ("neutral fats"), which usually contain different fatty acids in the same glycerol molecule. J. Am.- Oil. Chem Soc. Vol 62, page 730, (1985); and perfume. Cosmetics Vol 58, page 353, (1977); and Römpp, Chemie Lexikon, Ed. Jürgen FALBE and Manfred REGNITZ. 1990. 9th edition. Pages 1339 - 1342. Thieme Verlag Stuttgart, ISBN 3-13-734709-2.
Propylenglycol ist in in H.P. FIEDLER: Lexikon der Hilfsstoffe. 4. Auflage. 1996, ISBN 3-87193-173 auf den Seiten 1278 bis 1282 beschrieben. Propylene glycol is in HP FIEDLER: Lexicon of auxiliaries. 4th edition. 1996, ISBN 3-87193-173 on pages 1278 to 1282.
Polysorbate sind in H.P. FIEDLER: Lexikon der Hilfsstoffe, 4. Auflage. 1996. ISBN 3-87193-173 auf den Seiten 1251 bis 1252 beschrieben. Polysorbates are in HP FIEDLER: Lexicon of auxiliaries, 4th edition. 1996. ISBN 3-87193-173 described on pages 1251 to 1252.
Lecithine werden durch Extrahieren aus biologischem Material gewonnen. So umfaßt eine Lecithin - Fraktion aus Sojabohnen (dem gebräuchlichsten Rohstoff) z.B. Palmitinsäure, Stearinsäure, Palmitoleinsäure, Oleinsäure, Linolsäure u. Linolensäure. Normalerweise ist die gesättigte Fettsäure mit der primären, die ungesättigte mit der sekundären Hydroxy-Gruppe des Glyzerins verestert. Lecithine sind Bestandteile der Zellmembranen aller Lebewesen. In Wasser quellen Lecithine zunächst wie lyophile Kolloide auf. Später stellen sie durchsichtige, kolloidale Lösungen dar. Je nach Wassergehalt bilden sie unterschiedlichen Texturen, wobei die Lamellen aus Lipid - Doppelschichten gebildet werden. Bei höherem Wassergehalt entstehen Liposomen. Lit.: Pardun, Die Pflanzenlecithine, Augsburg: Verl. für Chem. Ind. (Ziolkowsky KG) 1988. Weitere Lecithine und deren Wirkung sind beschrieben in J. GAREISS et al. 1994. Pafümerie und Kosmetik, Vol. 10/94, Seiten 652 - 659. Hüthing GmbH Heidelberg. Lecithins are extracted from biological material. A lecithin fraction from soybeans (the most common raw material) comprises, for example, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid and the like. Linolenic acid. Normally the saturated fatty acid is esterified with the primary, the unsaturated with the secondary hydroxy group of the glycerol. Lecithins are components of the cell membranes of all living things. Lecithins initially swell in water like lyophilic colloids. Later, they represent transparent, colloidal solutions. Depending on the water content, they form different textures, whereby the lamellae are formed from lipid double layers. With higher water content, liposomes are formed. Lit .: Pardun, Die Pflanzenlecithine, Augsburg: Verl. Für Chem. Ind. (Ziolkowsky KG) 1988. Further lecithins and their effects are described in J. GAREISS et al. 1994. Pafumerie und Kosmetik, Vol. 10/94, pages 652 - 659. Hüthing GmbH Heidelberg.
Ein Gel zeichnet sich durch die folgenden Eigenschaften aus: Es handelt sich um ein formbeständiges, leicht deformierbares, an Flüssigkeit und gegebenenfalls Gasen reiches, disperses System aus mindestens zwei Komponenten. Römpp. Chemie Lexikon, Herausgeb. Jürgen FALBE und Manfred REGNITZ, 1990, 9. Auflage, Seite 1511, Thieme Verlag Stuttgart, ISBN 3-13-734709-2; und Pharm. Unserer Zeit Vol. 8, Seiten 179 bis 188. (1979): und Parfüm. Kosmet.. Vol. 58, Seiten 251 bis 253 (1977)A gel is characterized by the following properties: It is a dimensionally stable, easily deformable, liquid and possibly gas-rich, disperse system consisting of at least two components. Rompp. Chemistry Lexicon, Ed. Jürgen FALBE and Manfred REGNITZ, 1990, 9th edition, page 1511, Thieme Verlag Stuttgart, ISBN 3-13-734709-2; and Pharm. Unserer Zeit Vol. 8, pages 179 to 188. (1979): and perfume. Kosmet .. Vol. 58, pages 251 to 253 (1977)
Konservierungsmittel können in der wäßrigen Phase enthalten sein. Zu den Konservierungsmittel gehört zum Beispiel Benzoesäure. Aufgrund ihrer antimikrobiellen Eigenschaft ist Benzoesäure als Konservierungsmittel besonders geeignet. Preservatives can be contained in the aqueous phase. Preservatives include, for example, benzoic acid. Because of its antimicrobial properties, benzoic acid is particularly suitable as a preservative.
Die Zusammensetzung der Erfindung zeigt pharmakologische Wirkung und ist als therapeutischer Wirkstoff oder als Medikament einsetzbar.The composition of the invention shows and is pharmacological can be used as a therapeutic agent or as a medication.
Bevorzugt ist eine erfindungsgemäße Zusammensetzung zusammen mit mindestens einem physiologisch verträglichen, pharmakologischen Hilfsstoff oder Trägerstoff. Pharmakologische Hilfsstoffe und Trägerstoffe sind in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980) beschrieben.A composition according to the invention is preferred together with at least one physiologically compatible, pharmacological auxiliary or carrier. Pharmacological adjuvants and vehicles are described in Remington's Pharmaceutical Science, 15 th ed. Mack Publishing Company, Easton Pennsylvania (1980).
Die Zusammensetzung der Erfindung eignet sich zur Behandlung verschiedener
Indikationen. Bevorzugt ist eine Zusammensetzung der Erfindung als therapeutischer
Wirkstoff zur Behandlung von Rosacea, Altershaut. Melasma, Akne und /
oder Hautirritationen. Mehr bevorzugt ist eine Zusammensetzung der Erfindung
als therapeutischer Wirkstoff zur Behandlung von Rosacea. Altershaut.
Melasma. Akne und / oder Hautirritationen zusammen mit mindestens einem
physiologisch verträglichen, pharmakologischen Hilfsstoff oder Trägerstoff. Die
Behandlung umfaßt prophylaktische und therapeutische Maßnahmen.
Für diese therapeutische Wirkungen ist die geeignete Dosis unterschiedlich und hängt beispielsweise von der Konzentration der Einzelelemente in der pharmazeutischen Zusammensetzung ab, dem Wirt, der Art der Verabreichung und der Art und der Schwere der zu behandelnden Zustände abThe appropriate dose for these therapeutic effects is different and depends, for example, on the concentration of the individual elements in the pharmaceutical Composition, the host, the mode of administration and the Type and severity of the conditions to be treated
Die pharmazeutische Zusammensetzung der Erfindung kann mit den in der galenischen Pharmazie üblichen Zusätzen und/oder Trägersubstanzen nach an sich bekannten Methoden zu den üblichen topischen Applikationsformen verarbeitet werden. The pharmaceutical composition of the invention can be compared with those in the galenic pharmacy usual additives and / or carriers according to known methods processed to the usual topical forms of application become.
Eine pharmazeutische Zusammensetzung, welche Azelainsäure enthält, weist die folgende Rezeptur und die folgenden Verfahrensschritte auf:A pharmaceutical composition containing azelaic acid has the following recipe and the following process steps:
Benzoesäure und EDTA werden in üblichen Konzentrationen in 60 bis 70 Teilen Wasser gelöst. Anschließend wird eine Mischung von 1 Teil mittelkettigen Triglyceriden und 1,5 Teilen Polysorbat 80 unter Rühren hinzugegeben und homogenisiert (Voremulsion). 1 Teil Lecithin wird in 12 Teilen Propylenglycol eingebracht. Die entstandene Lösung wird in die Voremulsion eingerührt und homogenisiert. Nach Zugabe von 1 Teil Polyacrylsäure werden 15 Teile Azelainsäure in die entstandene pharmazeutischen Zusammensetzung eingebracht. Danach erfolgt die Ausrichtung des Gelbildners mit der notwendigen Menge an Natriumhydroxid - Lösung. Das resultierende Gel besitzt eine etwa 4-fach höhere Verfügbarkeit von Azelainsäure in lebenden Hautschichten und / oder Hautanhangsorganen.Benzoic acid and EDTA are in common concentrations in 60 to 70 parts Water dissolved. Then a mixture of 1 part medium chain Triglycerides and 1.5 parts of polysorbate 80 are added with stirring and homogenized (pre-emulsion). 1 part of lecithin is in 12 parts of propylene glycol brought in. The resulting solution is stirred into the pre-emulsion and homogenized. After adding 1 part of polyacrylic acid, 15 parts Azelaic acid introduced into the resulting pharmaceutical composition. Then the gel former is aligned with the necessary one Amount of sodium hydroxide solution. The resulting gel has an approximately 4 times higher availability of azelaic acid in living skin layers and / or skin appendages.
Die perkutane Resorption von Azelainsäure wurde aus erfindungsgemäßen
Hydrogel-Formulierungen im Vergleich zu Skinoren®-Creme untersucht. Das
Ziel der Studie war, die Bioverfügbarkeit von Azelainsäure in der Haut. die
Penetration von Azelainsäure durch die Haut sowie den dermalen Metabolismus
von Azelainsäure zu beschreiben. Dazu wurden verschiedene 14C-markierte
Azelainsäure enthaltende Zubereitungen im in vitro- Modell der FRANZ-Diffusionskammer
auf intakte Vollhaut von haarlosen Mäusen (MF1 hr/hr
Ola/Hsd; Züchter: Winkelmann, Deutschland) aufgetragen. Eine Menge von 10
bis 15 mg der folgenden Zusammensetzungen wurde auf ein Hautareal von 2
cm2 appliziert:
Der Zeitverlauf der 14C- Azelainsäure wurde im Akzeptor - Medium (Hepes Hanks Balanced Salt Solution: HHBSS), das unter der Haut entlang strömt, in zweistündigen Intervallen über einen Zeitraum von 24 Stunden gemessen. Weiterhin wurde am Ende eine jeden Experiments die Radioaktivität auf der Hautoberfläche, im Stratum corneum sowie in der restlichen Haut bestimmt. Um den Metabolismus von Azelainsäure in der Haut zu untersuchen, wurden Hautextrakte und ausgewählte Fraktionen von Akzeptor - Medium mittels Radiochromatographie (HPLC und radiometrischer Detektion) untersucht.The time course of the 14 C-azelaic acid was measured in the acceptor medium (Hepes Hanks Balanced Salt Solution: HHBSS), which flows under the skin, at two-hour intervals over a period of 24 hours. Furthermore, at the end of each experiment the radioactivity on the skin surface, in the stratum corneum and in the rest of the skin was determined. In order to investigate the metabolism of azelaic acid in the skin, skin extracts and selected fractions of acceptor medium were examined by means of radiochromatography (HPLC and radiometric detection).
Die am Ende des Experimentes in der Haut gefundene 14C- Azelainsäure wurde nur zu einem Anteil von 3 bis 11 % metabolisiert. Daher sind die Angaben über die Radioaktivität in der Haut praktisch mit der Konzentration unveränderter Azelainsäure gleichzusetzen.Only 14 to 11% of the 14 C-azelaic acid found in the skin at the end of the experiment was metabolized. Therefore, the information about radioactivity in the skin is practically equivalent to the concentration of unchanged azelaic acid.
Die folgende Tabelle enthält eine Zusammenfassung der Ergebnisse:
Im Vergleich zur Standard - Creme wurden mit dem erfindungsgemäßen Mittel deutlich höhere Azelainsäure - Konzentrationen in der Haut erzielt.In comparison to the standard cream with the agent according to the invention achieved significantly higher azelaic acid concentrations in the skin.
Claims (16)
- Composition that comprises the following features:(i) Azelaic acid as a therapeutic active ingredient,(iii) triacylglycerides,(iv) propylene glycol, and(v) polysorbates(vii) in an aqueous phase that comprises water and salts,
the composition comprises(ii) polyacrylic acid, and(vi) lecithin
and
that the composition is a hydrogel. - Composition according to claim 1, characterized in that the composition can be administered topically.
- Composition according to any one of the preceding claims, characterized in that the azelaic acid is present at a concentration of 5 to 20% by weight.
- Composition according to any one of the preceding claims, characterized in that the lecithin is soybean lecithin.
- Composition according to any one of the preceding claims, characterized in that the lecithin is present at a concentration of up to 1% by weight.
- Composition according to any one of claims 1 to 5, characterized in that the polyacrylic acid is present in the composition at a concentration of 0.5 to 2% by weight.
- Composition according to claim 6, characterized in that the polyacrylic acid is present in the composition at a concentration of 1 ± 0.25% by weight.
- Composition according to any one of claims 1 to 5, characterized in that the triacylglycerides are present in the composition at a concentration of 0.5 to 5% by weight.
- Composition according to claim 8, characterized in that the triacylglycerides are present in the composition at a concentration of 2 ± 1% by weight.
- Composition according to any one of claims 1 to 5, characterized in that the propylene glycol is present in the composition at a concentration of 5 to 15% by weight.
- Composition according to claim 10, characterized in that the propylene glycol is present in the composition at a concentration of 10 ± 2% by weight.
- Composition according to any one of claims 1 to 5, characterized in that the polysorbates are present in the composition at a concentration of 0.5 to 3% by weight.
- Composition according to claim 12, characterized in that the polysorbates are present in the composition at a concentration of 2 ± 0.5% by weight.
- Composition according to any one of the preceding claims for use as a medicament.
- Composition according to claim 14, characterized in that it comprises at least one physiologically acceptable pharmacological adjuvant or carrier.
- Composition according to claim 14 or 15 for use in treating rosacea, presbyderma, melasma, acne, and/or skin irritations.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI9830119T SI1032379T1 (en) | 1997-11-19 | 1998-11-18 | Composition with azelaic acid |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19753044 | 1997-11-19 | ||
DE19753044 | 1997-11-19 | ||
US7485098P | 1998-02-12 | 1998-02-12 | |
US74850P | 1998-02-12 | ||
DE19808086 | 1998-02-20 | ||
DE19808086 | 1998-02-20 | ||
PCT/EP1998/007370 WO1999025332A1 (en) | 1997-11-19 | 1998-11-18 | Composition with azelaic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1032379A1 EP1032379A1 (en) | 2000-09-06 |
EP1032379B1 true EP1032379B1 (en) | 2001-12-12 |
Family
ID=27217979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98962351A Expired - Lifetime EP1032379B1 (en) | 1997-11-19 | 1998-11-18 | Composition with azelaic acid |
Country Status (21)
Country | Link |
---|---|
US (1) | US6534070B1 (en) |
EP (1) | EP1032379B1 (en) |
JP (1) | JP3867123B2 (en) |
KR (1) | KR100534511B1 (en) |
AT (1) | ATE210438T1 (en) |
AU (1) | AU743437B2 (en) |
BR (1) | BR9814214B1 (en) |
CA (1) | CA2311128C (en) |
CZ (1) | CZ299116B6 (en) |
DE (2) | DE59802473D1 (en) |
DK (1) | DK1032379T3 (en) |
ES (1) | ES2169566T3 (en) |
HU (1) | HU226592B1 (en) |
IL (1) | IL136101A (en) |
IS (1) | IS2257B (en) |
NO (1) | NO327712B1 (en) |
PL (1) | PL202454B1 (en) |
PT (1) | PT1032379E (en) |
SK (1) | SK284338B6 (en) |
TR (1) | TR200001393T2 (en) |
WO (1) | WO1999025332A1 (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1633374T3 (en) * | 2003-06-10 | 2008-03-31 | Intendis Gmbh | Composition consisting of alkane dicarboxylic acids and a pharmaceutically active ingredient |
US20050026982A1 (en) * | 2003-06-10 | 2005-02-03 | Soenke Johannsen | Composition that consists of alkanedicarboxylic acids and a pharmaceutical active ingredient |
DE50305909D1 (en) * | 2003-10-13 | 2007-01-18 | Salama Zoser B | Pharmaceutical composition comprising oxoplatin and its salts |
DE10356288B4 (en) | 2003-11-28 | 2014-04-03 | Siemens Aktiengesellschaft | X-ray detector tray |
US20060204469A1 (en) * | 2005-03-09 | 2006-09-14 | Eric Spengler | Stable mixed emulsions |
WO2007040598A2 (en) * | 2005-09-19 | 2007-04-12 | Combe Incorporated | Stable emulsion systems with high salt tolerance |
KR100861978B1 (en) * | 2007-03-22 | 2008-10-07 | 한국콜마 주식회사 | Cosmetic compositon containing azelaic acid for treating acne skin and its manufacturing method thereof |
US8729108B2 (en) * | 2008-06-17 | 2014-05-20 | Christopher J Dannaker | Waterborne topical compositions for the delivery of active ingredients such as azelaic acid |
EP2201930A1 (en) | 2008-12-23 | 2010-06-30 | Intendis GmbH | Hydrogel composition for the treatment of dermatological disorders |
US20100247693A1 (en) * | 2009-03-24 | 2010-09-30 | Marini Jan L | Cosmetic formulation to treat rosacea telangiectasia |
PL217786B1 (en) * | 2009-05-28 | 2014-08-29 | P P F Hasco Lek Spółka Akcyjna | Gel containing azelaic acid and method for production of a gel containing azelaic acid |
BR112012003834A2 (en) | 2009-08-21 | 2017-08-08 | Targeted Delivery Tech Limited | methods for treating disorders and for treating fatty acid deficiency, hypertriglyceridemia or hypercholesterolemia and package |
DE102010021671A1 (en) | 2010-05-27 | 2011-12-01 | Intendis Gmbh | Azelaic acid-containing formulation with added pigment |
GB201205642D0 (en) * | 2012-03-29 | 2012-05-16 | Sequessome Technology Holdings Ltd | Vesicular formulations |
GB201208409D0 (en) * | 2012-05-14 | 2012-06-27 | Sequessome Technology Holdings Ltd | Vesicular formulations, kits and uses |
PL3316856T3 (en) | 2015-06-30 | 2021-10-25 | Sequessome Technology Holdings Limited | Blended formulations |
US11198831B2 (en) | 2019-01-31 | 2021-12-14 | Kvi Llc | Lubricant for a device |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3811081A1 (en) | 1988-03-30 | 1989-10-12 | Schering Ag | USE OF TOPIC APPLICABLE PREPARATIONS FOR THE TREATMENT OF AGING SKIN |
ATE117665T1 (en) * | 1990-11-14 | 1995-02-15 | Oreal | AMPHIPHILES, NON-IONIC DERIVATIVES OF GLYCERIN AND THE CORRESPONDING INTERMEDIATE PRODUCTS, METHOD FOR THEIR PRODUCTION AND COMPOSITIONS CONTAINING THEM. |
GB9316323D0 (en) | 1993-08-06 | 1993-09-22 | Procter & Gamble | Cosmetic compositions |
US5744155A (en) * | 1993-08-13 | 1998-04-28 | Friedman; Doron | Bioadhesive emulsion preparations for enhanced drug delivery |
AU5543294A (en) | 1993-10-29 | 1995-05-22 | Pharmos Corp. | Submicron emulsions as vaccine adjuvants |
ES2094688B1 (en) | 1994-08-08 | 1997-08-01 | Cusi Lab | MANOEMULSION OF THE TYPE OF OIL IN WATER, USEFUL AS AN OPHTHALMIC VEHICLE AND PROCEDURE FOR ITS PREPARATION. |
US5547989A (en) | 1994-08-19 | 1996-08-20 | Schering-Plough Healthcare Products, Inc. | Compositions for treating corns and calluses |
US5618522A (en) * | 1995-01-20 | 1997-04-08 | The Procter & Gamble Company | Emulsion compositions |
UY24246A1 (en) * | 1995-06-06 | 1996-06-14 | Neutrogena Corp | TROPIC VEHICLES CONTAINING SOLUBILIZED AND STABILIZED AZELAIC ACID |
-
1998
- 1998-11-18 ES ES98962351T patent/ES2169566T3/en not_active Expired - Lifetime
- 1998-11-18 AU AU17551/99A patent/AU743437B2/en not_active Expired
- 1998-11-18 CA CA002311128A patent/CA2311128C/en not_active Expired - Lifetime
- 1998-11-18 KR KR10-2000-7005430A patent/KR100534511B1/en not_active IP Right Cessation
- 1998-11-18 DE DE59802473T patent/DE59802473D1/en not_active Expired - Lifetime
- 1998-11-18 DE DE19881737T patent/DE19881737D2/en not_active Ceased
- 1998-11-18 EP EP98962351A patent/EP1032379B1/en not_active Expired - Lifetime
- 1998-11-18 BR BRPI9814214-3A patent/BR9814214B1/en not_active IP Right Cessation
- 1998-11-18 HU HU0004375A patent/HU226592B1/en unknown
- 1998-11-18 PL PL340631A patent/PL202454B1/en unknown
- 1998-11-18 DK DK98962351T patent/DK1032379T3/en active
- 1998-11-18 TR TR2000/01393T patent/TR200001393T2/en unknown
- 1998-11-18 AT AT98962351T patent/ATE210438T1/en active
- 1998-11-18 PT PT98962351T patent/PT1032379E/en unknown
- 1998-11-18 JP JP2000520766A patent/JP3867123B2/en not_active Expired - Lifetime
- 1998-11-18 IL IL13610198A patent/IL136101A/en not_active IP Right Cessation
- 1998-11-18 CZ CZ20001844A patent/CZ299116B6/en not_active IP Right Cessation
- 1998-11-18 US US09/554,738 patent/US6534070B1/en not_active Expired - Lifetime
- 1998-11-18 WO PCT/EP1998/007370 patent/WO1999025332A1/en active IP Right Grant
- 1998-11-18 SK SK708-2000A patent/SK284338B6/en not_active IP Right Cessation
-
2000
- 2000-05-09 IS IS5484A patent/IS2257B/en unknown
- 2000-05-12 NO NO20002487A patent/NO327712B1/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1032379B1 (en) | Composition with azelaic acid | |
DE3915617B4 (en) | Use of a cyclosporin-containing composition for topical application | |
DE69512685T3 (en) | AGENTS FOR THE ADMINISTRATION OF ACTIVE SUBSTANCES TO BZW. BY THE SKIN | |
EP1282446B1 (en) | Pharmaceutical and/or cosmetic composition containing an organosiloxane and a phospholipid | |
DE3853191T2 (en) | Drug carrier. | |
EP0616801A1 (en) | Process for preparing a liposome dispersion at high pressure | |
DE3713493A1 (en) | COSMETIC OR PHARMACEUTICAL AGENT BASED ON AN AQUEOUS DISPERSION OF LIPID BALLS | |
DE3713494A1 (en) | METHOD FOR PRODUCING A DISPERSION OF LIPID BALLS IN AN AQUEOUS PHASE AND DISPERSIONS AVAILABLE ACCORDING TO THIS METHOD | |
EP1014954A2 (en) | Transdermal therapeutic system | |
EP0256285A1 (en) | Pharmaceutical formulation and process for its preparation | |
EP0711557A1 (en) | Base for formulating pharmaceutical agents | |
EP0570829A1 (en) | Pharmaceutical composition for intravenous administration containing cyclosporin and method for its preparation | |
EP0945136B9 (en) | Topical pharmaceutical preparation comprising ciclosporin | |
DE19537012A1 (en) | Pharmaceutical preparation containing cyclosporin (s) for oral administration and process for its preparation | |
EP3568123B1 (en) | Introduction of hardly soluble and/or watersoluble active agents with lipid based nanoparticles/nanovesicles into a hydrophilic threedimensional network of cellulose | |
DE19900054A1 (en) | Taxane-containing stable and sterile emulsion and process for their preparation | |
WO2016166091A1 (en) | Natural-substance combination containing at least one glycyrrhetinic acid and at least one guggelsterone and use thereof for cosmetic applications | |
EP0651995B1 (en) | Cyclosporin(s) containing O/W emulsion for oral administration | |
EP0835100B1 (en) | Topical aciclovir preparation | |
DE69926633T2 (en) | INJECTABLE MEDICINE PREORMULATIONS OF PARTRICINE DERIVATIVES | |
DE4315921A1 (en) | Pharmaceutical prepn. contg. cyclosporin(s) for intravenous use | |
EP1633374B1 (en) | Composition consisting of alkane dicarboxylic acids and a pharmaceutically active ingredient | |
EP1913934A1 (en) | Emulgator-free plant oil containing an ophthalmic preparation | |
MXPA00004908A (en) | Composition with azelaic acid | |
DE19918644A1 (en) | Intradermal composition for local treatment of skin aging or wrinkles, comprising matrix containing estrogen and structure former to minimize systemic side-effects |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20000517 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20000513;LT PAYMENT 20000513;LV PAYMENT 20000513;MK PAYMENT 20000513;RO PAYMENT 20000513;SI PAYMENT 20000513 |
|
17Q | First examination report despatched |
Effective date: 20000927 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20000513;LT PAYMENT 20000513;LV PAYMENT 20000513;MK PAYMENT 20000513;RO PAYMENT 20000513;SI PAYMENT 20000513 |
|
REF | Corresponds to: |
Ref document number: 210438 Country of ref document: AT Date of ref document: 20011215 Kind code of ref document: T |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: GERMAN |
|
REF | Corresponds to: |
Ref document number: 59802473 Country of ref document: DE Date of ref document: 20020124 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) |
Effective date: 20020315 |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20020308 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2169566 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20020400974 Country of ref document: GR |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: SI Ref legal event code: IF |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: INTENDIS GMBH Free format text: SCHERING AKTIENGESELLSCHAFT#MUELLERSTRASSE 170/178#13353 BERLIN (DE) -TRANSFER TO- INTENDIS GMBH#MAX-DOHRN-STRASSE 10#10589 BERLIN (DE) Ref country code: GB Ref legal event code: 732E |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: SI Ref legal event code: SP73 Owner name: INTENDIS GMBH; DE Effective date: 20070213 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: PD4A Owner name: BAYER SCHERING PHARMA AG, DE Effective date: 20070518 Ref country code: PT Ref legal event code: PC4A Owner name: INTENDIS GMBH, DE Effective date: 20070518 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A |
|
NLS | Nl: assignments of ep-patents |
Owner name: INTENDIS GMBH Effective date: 20070522 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 18 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 19 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20171108 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20171114 Year of fee payment: 20 Ref country code: FR Payment date: 20171026 Year of fee payment: 20 Ref country code: FI Payment date: 20171109 Year of fee payment: 20 Ref country code: DK Payment date: 20171110 Year of fee payment: 20 Ref country code: MC Payment date: 20171129 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20171201 Year of fee payment: 20 Ref country code: SE Payment date: 20171113 Year of fee payment: 20 Ref country code: IE Payment date: 20171109 Year of fee payment: 20 Ref country code: NL Payment date: 20171031 Year of fee payment: 20 Ref country code: BE Payment date: 20171024 Year of fee payment: 20 Ref country code: PT Payment date: 20171116 Year of fee payment: 20 Ref country code: GB Payment date: 20171115 Year of fee payment: 20 Ref country code: IT Payment date: 20171123 Year of fee payment: 20 Ref country code: GR Payment date: 20171025 Year of fee payment: 20 Ref country code: CH Payment date: 20171114 Year of fee payment: 20 Ref country code: AT Payment date: 20171026 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CY Payment date: 20171020 Year of fee payment: 20 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 59802473 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EUP Effective date: 20181118 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MK Effective date: 20181117 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20181117 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MK Effective date: 20181118 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MK9A |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: EUG |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK07 Ref document number: 210438 Country of ref document: AT Kind code of ref document: T Effective date: 20181118 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20181127 Ref country code: IE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20181118 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20181117 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20200904 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20181119 |